tbuckley/cabot-search huggingface dataset:
Abstract 5965: The effectiveness of health care professional training on the legal issues impacting individuals diagnosed with cancer to improve patient quality of life
Authors: Madison McMahon Ward, Joanna Fawzy Morales, Monica Fawzy Bryant
Journal: Cancer Research (2022)

Abstract A cancer diagnosis may carry with it a variety of legal issues, including navigating insurance, government benefits, employment, and consumer rights. These legal issues can cause people unnecessary worry, confusion, and stress, and can be overwhelming. The Insurance and Finance Intensive provides health care professionals tools to proactively identify the presence of cancer-related legal, insurance, and financial issues facing their patients. Additionally, the training helps health care professionals to offer referrals to appropriate legal and related resources, once those issues are identified. Oncology health care professionals participated in an eight-hour comprehensive training. Attendees were provided with substantive information about cancer-related legal issues, such as identifying health insurance options, navigating taking time off work and accessing disability insurance, and managing finances. A follow-up survey was sent to past 2020 and 2021 Intensive attendees (n=126), to measure the effectiveness of the training and to address additional questions and difficult case studies. Ninety-four percent of survey respondents indicated that they changed their behavior or practice based on what they learned at the training. Ninety-four percent of survey respondents strongly agreed or agreed that the information provided by the training helped reduce the financial burden that their patients and families experience after a cancer diagnosis. Ninety-seven percent of respondents strongly agreed or agreed that the information provided by the training improved the quality of life of their patients and families. The Insurance &amp; Finance Intensive successfully provided health care professionals with valuable information on the practical and legal issues that impact individuals diagnosed with cancer. It is recommended that more health care professionals participate in this training to mitigate the financial burden of a diagnosis and improve the quality of life of their patients. Citation Format: Madison McMahon Ward, Joanna Fawzy Morales, Monica Fawzy Bryant. The effectiveness of health care professional training on the legal issues impacting individuals diagnosed with cancer to improve patient quality of life [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5965.
Abstract 5490: Comparative activation of cellular ISR and cell death induction by p53 pathway restoring small molecules
Authors: Xiaobing Tian, Wafik S. El-Deiry
Journal: Cancer Research (2022)

Abstract Restoration of the p53 pathway has been a long-term goal of the field of cancer research as an approach to treat tumors with mutated p53 and aggressive clinical behavior. In general, p53- pathway-restoring can be achieved by small molecules through p53-dependent or p53-independent ways. For short, hereafter p53-independent restoration of p53-pathway-signaling is also referred as ‘restoration of p53 pathway’. To perform a comparative activation of p53 target genes, novel compounds PG3 and PG3-Oc that activate a subset of p53-target genes in a p53-independent manner, and four known mutant p53-activating compounds were included (ZMC1, APR-246, CP-31398 and Ellipticine). Nutlin-3a was used as a negative control. PG3 and PG3-Oc induced significant upregulation of p21, PUMA (p53 upregulated modulator of apoptosis), and DR5 consistently in five tested cancer cell lines with various p53 status through ATF4 (Activating transcriptional factor 4) via the ISR in a p53-independent manner. However, mutant p53-targeting compounds induced the expression of the three p53 target genes and ATF4 in a highly variable and cell type-dependent manner. PG3 treatment activated ATF4 through the ISR via kinase HRI (Heme-regulated inhibitor). ATF4 mediated the upregulation of PUMA, p21 and NAG-1 (Nonsteroidal anti-inflammatory drug-activated gene 1). We identified PUMA-mediated cell apoptosis through activation of caspase-8 in HT29 cells and possibly caspase-10 in SW480 cells. In summary, we provide a new mechanism that PG3 induced cell death via an HRI/ATF4/PUMA axis that may be helpful in understanding drug efficacy. Citation Format: Xiaobing Tian, Wafik S. El-Deiry. Comparative activation of cellular ISR and cell death induction by p53 pathway restoring small molecules [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5490.
Abstract 383: ONCR-021 as a systemic intravenous synthetic RNA virus immunotherapy for the repeat treatment of cancer
Authors: Jeffrey Bryant, Agnieszka Denslow, Jacqueline Hewett, Lingxin Cong, Ana De Almeida, Jennifer Lee, Judy Jacques, Sonia Feau, Daniel. Wambua, Adrienne Yanez, Pam Shou-Ping Wang, Jessica Deterling, Matthew Scott, Jason Auer, Brian B. Haines, Christophe Quéva, Lorena Lerner, Edward M. Kennedy
Journal: Cancer Research (2022)

Abstract Oncolytic viruses (OV) have shown great potential to improve clinical outcomes when dosed intratumorally, however, their therapeutic efficacy when intravenously administered is likely limited by the rapid emergence of neutralizing antibodies. To overcome this limitation, we developed Synthetic RNA viruses consisting of a replication competent viral genomic RNA (vRNA) encapsulated within a lipid nanoparticle (LNP) for IV administration. Upon dosing and delivery of this infectious RNA payload, the vRNA initiates viral replication and virus production in neoplastic cells leading to oncolysis and tumor destruction. This formulation enables repeat intravenous dosing of a replication competent oncolytic virotherapy even in presence of circulating neutralizing antibody to the virus. Here we present ONCR-021, an LNP formulation of Coxsackievirus A21 (CVA21) vRNA. ONCR-021 vRNA encodes a novel ICAM1-dependent strain of CVA21 that results in greater in vitro and in vivo oncolysis compared to the previously described CVA21 Kuykendall strain. ONCR-021 is broadly oncolytic in cancer cell lines in vitro and is intended for clinical development in NSCLC, RCC, and HCC based upon the viral tropism. IV-administration of ONCR-021 vRNA results in rapid initiation of viral replication, oncolysis, and potent anti-tumor efficacy, even in the presence of circulating CVA21 neutralizing antibodies. This efficacy is principally driven by CVA21 amplification in situ after delivery to tumor cells and we demonstrate viral replication, virion production and spread within the tumor after dosing. We also observe only modest and transient production of CVA21 in healthy tissues of transgenic mice expressing the CVA21 entry receptor human ICAM1. Consistent with these findings, high doses levels of ONCR-021 were well-tolerated in this model. Altogether, these preclinical data support the development of ONCR-021, a novel synthetic oncolytic virus designed to overcome the challenges of repeat intravenous administration of viral immunotherapy for the treatment of disseminated cancers. Citation Format: Jeffrey Bryant, Agnieszka Denslow, Jacqueline Hewett, Lingxin Cong, Ana De Almeida, Jennifer Lee, Judy Jacques, Sonia Feau, Daniel. Wambua, Adrienne Yanez, Pam Shou-Ping Wang, Jessica Deterling, Matthew Scott, Jason Auer, Brian B. Haines, Christophe Quéva, Lorena Lerner, Edward M. Kennedy. ONCR-021 as a systemic intravenous synthetic RNA virus immunotherapy for the repeat treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 383.
Dual roles of drug or its metabolite−protein conjugate: Cutting‐edge strategy of drug discovery using shotgun proteomics
Authors: Shilin Gong, Xiaolan Hu, Shengshuang Chen, Baoqing Sun, Jian‐Lin Wu, Na Li
Journal: Medicinal Research Reviews (2022)

Abstract Many drugs can bind directly to proteins or be bioactivated by metabolizing enzymes to form reactive metabolites (RMs) that rapidly bind to proteins to form drug−protein conjugates or metabolite−protein conjugates (DMPCs). The close relationship between DMPCs and idiosyncratic adverse drug reactions (IADRs) has been recognized; drug discovery teams tend to avoid covalent interactions in drug discovery projects. Covalent interactions in DMPCs can provide high potency and long action duration and conquer the intractable targets, inspiring drug design, and development. This forms the dual role feature of DMPCs. Understanding the functional implications of DMPCs in IADR control and therapeutic applications requires precise identification of these conjugates from complex biological samples. While classical biochemical methods have contributed significantly to DMPC detection in the past decades, the low abundance and low coverage of DMPCs have become a bottleneck in this field. An emerging transformation toward shotgun proteomics is on the rise. The evolving shotgun proteomics techniques offer improved reproducibility, throughput, specificity, operability, and standardization. Here, we review recent progress in the systematic discovery of DMPCs using shotgun proteomics. Furthermore, the applications of shotgun proteomics supporting drug development, toxicity mechanism investigation, and drug repurposing processes are also reviewed and prospected.
Levelling up the UK: is the government serious about reducing regional inequalities in health?
Authors: Rob Ralston, Katherine Smith, Clementine Hill O’Connor, Ally Brown
Journal: BMJ (2022)

The recent white paper lacks innovation, policy levers, and, crucially, long term investment, say Rob Ralston and colleagues The Levelling Up white paper,1 released in February 2022 after major delay, outlines the UK government's much anticipated strategy for tackling regional inequality. The centrepiece of the government's reform agenda, "levelling up" is presented as a solution to the UK's longstanding and serious geographical inequalities (box 1). Although levelling up is already permeating political and media discourse,10 the white paper is the first attempt to translate this broad idea into specific policy commitments to tackle place based inequalities: white papers set out proposals for future legislation. Box 1 ### UK Health inequalities—social, economic, and commercial determinants Health inequalities (or health inequities) are systemic variations in health between groups defined by socioeconomic, ethnic, or geographical characteristics that are socially determined, modifiable, and, therefore, unfair.2 Health inequalities are caused by the unequal distribution of wider determinants of health, including housing, employment, education, and wealth, as well as by inequalities in exposure to commercial influences such as the availability of alcohol, tobacco, gambling, and unhealthy food).3 Health inequalities are pervasive in many countries, but the UK has particularly stark differences in health between socioeconomic groups and areas.4 In 2018-20, for example, men in the most deprived 10th of the population in England had healthy life expectancies 18.4 years shorter than men in the least deprived 10th,5 while in Scotland, the equivalent gap was over 23 years, and premature death in Scotland's most deprived areas was four times higher than in the least deprived areas. A government led programme of austerity beginning in 2010 has worsened inequalities in recent years.6 #### Unequal impact of covid-19 Covid-19 infected, killed, and impoverished unequally by socioeconomic group, area, and ethnicity.7 The extent of differences in mortality by ethnic group drew attention to this previously under examined … RETURN TO TEXT
Optimising both disease control and glucocorticoid dosing is essential for bone protection in patients with rheumatic disease
Authors: Edgar Wiebe, Dörte Huscher, Désireé Schaumburg, Andriko Palmowski, Sandra Hermann, Thomas Buttgereit, Robert Biesen, Gerd-Rüdiger Burmester, Yannick Palmowski, Maarten Boers, John H Stone, Christian Dejaco, Frank Buttgereit
Journal: Annals of the Rheumatic Diseases (2022)

Objectives Inflammatory rheumatic and musculoskeletal diseases (iRMDs) are associated with increased systemic bone loss that is mediated by chronic inflammation, treatment with glucocorticoids (GCs) and other factors. Our objective was to analyse the impact of variables that influence osteoporosis (OP) in patients with iRMD treated with GC. Methods Rh-GIOP (acronyme) is a prospective observational cohort study investigating bone health in consecutive patients with iRMD and current or prior GC treatment. We present an analysis of the patients’ baseline data here. Bone mineral density (BMD) measured by dual X-ray absorptiometry was the primary outcome. Multivariable linear regression models were performed to identify variables associated with BMD. Results Data from 1066 patients with iRMD were analysed. GC doses of &lt;5 mg prednisone equivalent per day, cumulative dose and duration of GC therapy were not associated with negative effects on BMD. Dosages of ≥5 mg/day lost their negative association with BMD after adjustment for confounders. When subanalysing patients with exactly 5 mg/day, no negative effect was seen. For patients with rheumatoid arthritis (RA), GC doses of &gt;7.5 mg/day showed a negative association with BMD overall, but this effect seemed to be specific only to patients with moderate or high disease activity (Disease Activity Score 28–C reactive protein &gt;3.2). Conclusions GCs of ≤5 mg/day did not seem to be associated with a reduction of BMD in patients with iRMD and current or prior exposure to GC. This is most likely due to the dampening of inflammation by GC, which exerts a mitigating effect on the risk of OP. In RA, current GC doses of &gt;7.5 mg/day were negatively associated with BMD, but only in patients with moderate to high disease activity. Trial registration number NCT02719314 .
Abstract 990: Functional genomic screen of kinases in high-grade serous ovarian cancer metastasis
Authors: Emilee Nicole Kotnik, Elena Lomonosova, Daniel Wilke, Gregory Longmore, Katherine C. Fuh
Journal: Cancer Research (2022)

Abstract High-Grade Serous Ovarian Cancer (HGSC) is a highly metastatic cancer with the majority of patients presenting in advanced stages. Currently there are limited targeted treatment options for patients, especially for women with high metastatic tumor burden. In order to improve patient outcomes, we have aimed to identify and characterize kinases that may regulate the steps of metastasis in HGSC. Kinases in particular serve as actionable targets because we can design inhibitors of the kinases and their ligands. Several kinases, such as tyrosine kinases and aurora kinases, have previously been implicated in ovarian cancer and seem to influence tumor cell metastasis. Our lab performed a functional genomic screen on 719 kinases in a tumor cell attachment and proliferation assay. In this screen, we cultured primary fibroblasts from patient omentum and plated them on top of a collagen and fibronectin matrix, to mimic the tumor microenvironment. We used siRNA transfection reagents, which were plated atop the fibroblasts along with GFP-labeled ovarian cancer cells that were then incubated with the other cell layers for 72 hours. Based on the florescence intensities, we calculated median average deviations (MAD) values normalized to controls to be a measure of ovarian cancer cell attachment and proliferation. This screen was replicated in 3 ovarian cancer cell lines, including OVCAR8, ES2, and A2780, across 9 panels for 2 libraries. Both libraries had 2 distinct siRNAs for each kinase, in total 4 siRNAs per kinase. From this initial screen, we have identified 20 candidate kinases to validate based on having significantly negative MAD values in at least two cells lines in the screen. Candidate kinases have been validated by knock-down in two ovarian cancer cell lines, ES2 and OVCAR8, and assessed on their ability to migrate in a wound-healing assay. The top kinases will be further studied for their ability to regulate the steps of tumor cell metastasis and the mechanisms that allow them to promote metastasis. Our study aims to identify actionable targets that influence these steps of metastasis, so we can develop drugs that target metastatic tumors and serve as maintenance therapies to help prevent further metastasis, mediate chemoresistance, and improve patient outcomes. Citation Format: Emilee Nicole Kotnik, Elena Lomonosova, Daniel Wilke, Gregory Longmore, Katherine C. Fuh. Functional genomic screen of kinases in high-grade serous ovarian cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 990.
Abstract 5920: Multi-cancer early detection with a spectroscopic liquid biopsy platform
Authors: James M. Cameron, Alexandra Sala, Georgios Antoniou, Paul M. Brennan, Justin J. A. Conn, Siobhan Connal, David S. Palmer, Benjamin R. Smith, Matthew J. Baker
Journal: Cancer Research (2022)

Abstract The development of a robust multi-cancer early detection (MCED) test would be transformational within the cancer diagnostics field, as earlier detection is vital to inhibit disease progression, improve patient prognosis and reduce mortality rates. In this large-scale spectroscopic study, we present the Dxcover® Cancer Liquid Biopsy, the world’s first infrared spectroscopy-based blood test for the early detection of multiple cancers. The full cohort (n=2094) was comprised of patients with a confirmed cancer diagnosis (n=1543), symptomatic non-cancer patients (n=460) and healthy volunteers (n=91). For the cancer versus non-cancer classification, receiver operating characteristic analysis produced a mean curve with an area under the curve (AUC) value of 0.86. When adjusted for greater sensitivity, our model achieved 90% sensitivity with 61% specificity, and yielded a sensitivity of 56% with 91% specificity when tailored for higher specificity. We also tuned for maximized sensitivity or specificity, whilst the other parameter was fixed above a minimum value of 45% for the cross-validation result, based upon performance levels of currently available clinically benchmarked tests. This resulted in a 94% sensitivity where specificity was 47%, and a 94% specificity with 48% sensitivity. The overall detection rates were 93% for stage I, 84% for stage II, 92% for stage III and 95% for stage IV for the sensitivity-tuned model. The specificity-tuned model detected 90% of non-cancer patients accurately, resulting in few false negatives (54/551). For the binary classifiers of individual cancer types against symptomatic control patients, promising AUC values were reported for all cancers: brain (0.90), breast (0.74), colorectal (0.91), kidney (0.91), lung (0.90), ovarian (0.85), pancreatic (0.81) and prostate (0.85). Importantly, the detection rates did not vary significantly according to cancer stage, suggesting the technology is very effective at detecting early-stage tumors, which is a necessity for MCED tests. Citation Format: James M. Cameron, Alexandra Sala, Georgios Antoniou, Paul M. Brennan, Justin J. A. Conn, Siobhan Connal, David S. Palmer, Benjamin R. Smith, Matthew J. Baker. Multi-cancer early detection with a spectroscopic liquid biopsy platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5920.
Abstract 1342: Evaluating the role of antibody in pancreatic tumorigenesis
Authors: Jeremy Foote
Journal: Cancer Research (2022)

Abstract Introduction: Infiltrating pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal human malignancies, with an overall 5-year survival rate of 10%. The PDAC tumor microenvironment (TME) is characterized by a fibroinflammatory response mediated by a complex mix of cancer-associated fibroblast (CAF) subsets resulting significant deposition of extracellular matrix (ECM), poor vascularization, T cell exclusion, and recruitment of immune-suppressive myeloid cells. Collectively, these factors contribute to a resistance to aggressive chemotherapeutics and failure of checkpoint inhibitors. Preclinical studies as well as clinical efforts designed to deplete the dense tumor stroma or ECM have been successful, but unexpectedly accelerated tumor progression underscoring critical gaps in our understanding of the dynamics between tumor, stromal elements, and infiltrating immune cell subsets. Rationale: In some cancer subtypes, B cells have been shown to suppress cancer progression through secretion of antibodies targeted to aberrantly expressed self-, stress-associated-, or tumor-specific antigens on neoplastic cells. A considerable body of literature also indicates that B cells may play a role in promotion of pancreatic tumor progression, however, the role of antibodies in PDAC progression is unclear. The major objective of our studies is to understand the significance of anti-tumor antibody responses in pancreatic tumorigenesis. Methods: To address this question, we crossed the spontaneous mouse model of pancreatic cancer where Pdx1 drives Cre-mediated activation of a mutant KrasG12D allele on a heterozygous Tp53+/FL mutant background (KPC-WT mice) with animals that retain B cells that lack the ability to secrete antibody of any immunoglobulin (Ig) isotype (KPC-μS-AID mice). Results: Kaplan-Meier survival studies demonstrate that loss of all circulating antibody accelerates progression to lethal PDAC in KPC-μS-AID versus KPC-WT mice (median survival of 3- versus 5-months, respectively), with increased incidence of lung and liver metastases. Further, loss of circulating antibodies increased the density of intratumoral neutrophils, reduced numbers of podoplanin+ CAFs and reduced ECM density. IgG subclass antibodies were localized at higher densities within stroma/ECM in pancreata from both mice and surgically resected tumor specimens from human PDAC patients. Loss of AID-dependent class switched antibodies similarly accelerated lethal PDAC in KPC-AID versus KPC-WT mice. Conclusions: These findings implicate class-switched antibodies in delaying pancreatic tumor progression through potential regulation of intratumoral neutrophil density and ECM production within the PDAC TME. Citation Format: Jeremy Foote. Evaluating the role of antibody in pancreatic tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1342.